Angiotensin II (AII) is an octapeptide hormone which is a component of the renin-angiotensin system. In addition to being a circulating hormone which affects the cardiovascular system, the adrenal cortex, the peripheral autonomic nervous system, and the kidneys, AII is also known to affect the central nervous system. AII is now believed to act as a neuropeptide in the central nervous system (CNS) and may modulate the release and subsequent action of other neurotransmitters (Unger et al. (1988) Circulation 77 (Suppl. I):40-54).
Specific high affinity receptors for AII have been identified and localized in different regions of the CNS (Mann (1982) Exp. Brain Res. 4 (Suppl):242). Stimulation of AII receptors in the CNS elicits a complex, but highly reproducible and concerted pattern of behavioral, cardiovascular, and endocrine responses (Fitzsimons (1980) Rev. Physiol. Biochem. Pharmacol, 87:117). These include CNS-induced elevation of blood pressure, increased drinking and sodium appetite, and release of antidiuretic hormone, oxytocin, luteinizing hormone, and prolactin (Scholken et al. (1982) Experientia 38:469). The CNS effects of AII could lead to hypertension and other cardiovascular diseases through inhibition of the baroreceptor reflex, increase in salt consumption, volume expansion, and increased peripheral resistance. Besides the cardiovascular system, AII may also influence the reproductive system and other brain functions, such as memory (Koller et al. (1975) Neuroscience Lett. 14:71-75).
The major functions of AII in the CNS can be classified into three groups which may share, at least in part, overlapping mechanisms of action. The first major function of AII in the CNS is regulation of body fluid volume in response to hypovolemia, involving, for example, regulation of thirst, blood pressure increases, vasopressin release, sodium appetite increase, adrenocorticotropic hormone (ACTH) release, and aldosterone release (Unger et al. (1988) Circulation 77 (Suppl I):40-54, and references cited therein). This CNS function of AII is closely related to the peripheral role of AII in hypertension.
A second function of AII in the CNS, although less well defined, is the regulation of gonadotrophic hormone releasing hormones and pituitary hormones during the reproductive cycle and pregnancy (Unger et al., supra).
A third possible CNS function of AII is a synaptic function. AII appears to interact with neurotransmitters such as acetylcholine (ACH), catecholamines, serotonin, and other neuroactive peptides (Unger et al., supra). Although the amount of data supporting this CNS function of AII is limited, published results suggest that increased AII activity in the brain exerts an inhibitory effect on cholinergic neurons resulting in impaired cognitive performance. Therefore, compounds that inhibit AII biosynthesis, or block AII receptor activation may enhance cognition.
The role of peptides in learning and memory was initially investigated by D. DeWied in the late 1960's and early 1970's. This led Morgan and Routtenberg Science (1977) 196:87-89) to investigate the role of AII in mediating retention of a passive avoidance (PA) response in rats. These authors demonstrated that rats injected with AII into the dorsal neostriatum, a brain area that has a high concentration of AII as well as precursors and metabolic enzymes for AII biosynthesis, showed a disruption in retention of a PA response. The authors demonstrated specificity of the response in terms of both the location in the brain, and the peptide used (unlike AII, thyrotropin releasing hormone or lysine-8-vasopressin had no effect). This study showed that increased AII in the dorsal neostriatum results in a cognitive impairment which is most likely related to AII modulation of neuronal activity that is necessary for consolidation of newly acquired information.
A different approach for investigating the behavioral effects of AII in the CNS was taken by Koller et al. (Neuroscience Letters (1975) 14:71-75). These authors injected renin into the lateral ventricle of the brain (IVT) and measured increases in AII in cerebrospinal fluid (CSF); AII levels increased from 40 to about 5000 fmol per mL. This increase in AII was accompanied by a disruption of avoidance learning. These results suggested that renin-stimulated biosynthesis of AII could disrupt memory. Administration into the IVT of the angiotensin converting enzyme (ACE) inhibitor SQ 14225 (captopril) prior to the renin injection, prevented the renin-induced avoidance disruption. Applicants have also found that renin administered IVT produces a dose-related amnesia in a PA task, which is prevented by IVT administration of the ACE inhibitor captopril. These results suggest that increased AII levels in the brain lead to a disruption of learned avoidance. This amnesia can be achieved by direct administration into a discrete brain area of either AII or renin, an enzyme involved in endogenous AII biosynthesis.
In the literature on the neuropathology and neurochemistry of Alzheimer's disease (AD), there are two reports of altered levels of dipeptidyl carboxypeptidase (angiotensin-converting enzyme, ACE) in human CSF and brain tissue. Arrequi et al. (J. Neurochemistry (1982) 38:1490-1492) found increased ACE activity in the hippocampus, parahippocampal gyrus, frontal cortex, and caudate nucleus in AD patients. Zubenko et al. (Biol. Psych. 21:1365-1385 (1986) found a correlation between levels of ACE in the CSF and the severity of AD. Whether the alterations in ACE cause the progression of dementia or are correlates of the disease progress remains unknown.
Recent evidence that inhibition of ACE can have a modulatory effect on learning and memory was reported by Usinger et al. (Drug Dev. Research 14:315-324 (1988); also European Patent Application, EP 307,872 to Hoechst, published Mar. 22, 1989).
Similar results were reported by Costall et al. (Pharmacol. Biochem. Behav. 33:573-579 (1989)) using the ACE inhibitor captopril. These authors demonstrated that subchronic treatment with captopril increased the rate of acquisition of light/dark habituation performance. Further, anticholinergic scopolamine-induced disruption of performance in this test model was prevented by daily treatment with captopril.
The ACE inhibitor SQ 29852 has also been reported to provide protective effects on memory of previously learned tasks and to ameliorate, at least in part, an anticholinergic effect on performance (European Patent Application EP 288,907 to Squibb, published Nov. 2, 1988).
The AT.sub.2 selective antagonist PD123177 has been reported by Brix and Haberl (The FASEB Journal 6(4):A1264, 1992) to block the pial arterial dilation induced by angiotensin II in a rat cranial window preparation monitored by intravital microscopy. This suggests that PD123177 may have a role in modify cerebral blood flow.
The AT.sub.2 selective antagonist PD123177 also has been reported by Matsubara et al. (The FASEB Journal 6(4):A1859, 1992) to block the angiotensin II induced inhibition of trypsin activated collagenase in rat heart myocytes suggesting an effect in cardiac remodeling in cardiac failure.
The AT.sub.2 selective antagonist CGP42112A has been reported by LeNoble et al. (The FASEB Journal 6(4):A937, 1992) to block the increase in microvascular density induced by angiotensin II in the chick chorioallantoic membrane preparation suggesting a possible anti-angiogenesis effect of this class of compounds.
Evidence for a role of AII in cholinergic function was also reported by Barnes et al. (Brain Research 491:136-143 (1989)), who examined the effect of AII in an in vitro model of potassium stimulated release of [.sup.3 H]ACh. AII, but not AI, reduced potassium-stimulated release of ACh without effects on basal levels. This effect was antagonized by the AII antagonist [1-sarcosine, 8-threonine]angiotensin II. These results suggest that AII can inhibit the release of ACh in the entorhinal cortex of rat brain.
The results summarized above suggest that increased AII activity in the brain may exert an inhibitory effect on cholinergic neurons, resulting in impaired cognitive performance. Thus, compounds that block AII receptor activation may enhance cognitive performance.
Carini and Duncia, U.S. Ser. No. 050,341, filed May 22, 1987, which is a continuation-in-part of U.S. Ser. No. 884,920, filed Jul. 11, 1986, disclose angiotensin II receptor blocking imidazoles (also EP 0253 310, published 20.01.88, and EP 0324 377, published 19.07.89).
Blankley et al., U.S. Pat. No. 4,812,462, issued Mar. 14, 1989, to Warner-Lambert, disclose 4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine derivatives, which are said to be useful for the treatment of hypertension.
Ardecky et al., U.S. Pat. No. 5,091,390, issued Feb. 25, 1992, discloses 4,5,6,7-tetrahydro-1H-imidazo(4,5-c)-pyridines useful for treating disorders of mammals mediated by AII type-2 receptors in the central nervous system.
Takasugi et al., U.S. Pat. No. 5,059,608, issued Oct. 22, 1991, to Fujisawa, disclose a bicyclic amine compound and a process for the preparation thereof, useful as an anticonvulsant and for treatment of delayed neuronal death.
Anderson et al., EPO 0,401,676, published Dec. 12, 1990, to Bio-Mega, disclose enzyme inhibitors which are peptide derivatives useful in combating HIV infections or for treating hypertension or congestive heart failure. Structure 3 on page 6 is a tetrahydroisoquinoline, and is used as an intermediate in making the peptides of Anderson'patent publication.